Chronic benzodiazepine administration. III. Upregulation of gamma-aminobutyric acidA receptor binding and function associated with chronic benzodiazepine antagonist administration.

Chronic administration of a benzodiazepine agonist appears to downregulate benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptor function. To examine the effects of chronic treatment with a benzodiazepine antagonist, we administered Ro15-1788, 1, 2 and 5 mg/kg/day to mice via implanted s.c. osmotic pumps for 1 to 14 days. Plasma and cortex (CX) concentrations of Ro15-1788 remained constant between days 1 and 7, indicating no change in pharmacokinetics. Open-field activity studies showed no change in distance traveled or ambulatory time at days 1, 2 and 4, but an increase in both parameters at days 7 and 14 in mice receiving Ro15-1788, 2 mg/kg/day. Benzodiazepine receptor binding was unchanged in CX, cerebellum (CB), hypothalamus, hippocampus and ponsmedulla at 1, 2 and 4 days at a dose of 2 mg/kg/day. Binding was increased in CX, CB and hippocampus at day 7 compared to days 1 and 2, and remained elevated at day 14. Similar results were observed at Ro15-1788 doses of 1 and 5 mg/kg/day. Benzodiazepine binding assessed in vitro in CX and CB also was increased at day 7 compared to day 1, due to an increase in receptor number rather than a change in apparent affinity. Binding of t-[35S]butylbicyclophosphorothionate to the chloride channel site in CX after Ro15-1788, 2 mg/kg/day, was increased at days 7 and 14 compared to days 1, 2 and 4 and controls due to an increase in number of binding sites. t-Butylbicyclophosphorothionate binding in CB was unchanged throughout.(ABSTRACT TRUNCATED AT 250 WORDS)